Hepatitis C virus infection most often leads to chronic hepatitis and about one third of patients develop cirrhosis and a minority of those develops hepatocellular carcinoma. The infection is also associated with fatty liver disease. HCV RNA replication and maturation activities are associated with the altered endoplasmic reticular (ER) membranes modified membranous structures including lipid droplets. Recent work from several laboratories indicates role of cellular lipid/fatty acid synthetic pathways in viral replication, morphogenesis and secretion processes. These viral activities induce ER stress, which manifests as an unfolded protein response (UPR). Furthermore, these activities alter calcium homeostasis and induce oxidative stress in HCV expressing cells. One of the consequences of the calcium signaling is the activation of calcium-dependent calpain proteases. The effect of HCV-induced UPR in CD1d expression will be examined in HCV infection in response to ER stress. CD1d processing and lipid antigen loading is catalyzed by microsomal triglyceride transfer protein (MTP) and HCV gene expression regulates MTP activity in the ER. Thus, HCV-induced UPR affects innate immunity. In this study, we propose to investigate the mechanism(s) by which HCV-induced ER stress/UPR response alters the course of intracellular events. We further propose to investigate the role of activated components of the UPR in the viral infectious processes. These studies will provide unique insights into the mechanisms of liver disease pathogenesis associated with HCV infection. PUBLIC HEALTH RELEVANCE: Hepatitis C virus infection is the leading cause of chronic liver disease, and infection can progress to cirrhosis, steatosis, and hepatocellular carcinoma. HCV gene expression induces an ER stress response, which activates a whole host of cellular factors and functions that manifests in liver disease pathogenesis. In this study, we propose to investigate the impact of ER stress response/unfolded protein response in affecting lipid metabolic pathways, cellular proteases, which in turn affect viral functions including replication, morphogenesis/secretion and ultimately in liver disease pathogenesis.